1. Field of the Invention
The present invention is directed to a dialysis system and more specifically to a method and apparatus for analyzing and altering the component structure of a complex reference fluid, such as blood, by use of a dialysis system. The present invention is also directed to a method and apparatus which enables the determination of the concentration of a low-molecular-weight compound in a complex fluid.
2. Discussion of the Prior Art
Several methods are known for determining the component structure of a complex fluid. For purposes of this invention a complex fluid is a fluid medium which contains a variety of components having different molecular weights. Non-limiting examples of complex fluids include blood, biological culture media such as fermentation liquids, and air. For purposes of explanation only, the present invention will be primarily directed to a blood dialysis system. However, it should be understood that the device of the present invention has far reaching potential beyond blood dialysis. Examples of other uses are specified elsewhere in this text.
One well known procedure for determining the component structure of, for example, blood is to withdraw the blood for analysis under a microscope or by other suitable means such as spectrophotometric analyzers, etc. This method is highly useful for a variety of blood tests. However, successfully withdrawing blood from a patient without insulting the integrity of the blood is a difficult procedure. For example, when exposed to the atmosphere, blood clots quickly which could alter test results. Further, any time blood is withdrawn by means of a pump system, the corpuscular components such as the red blood cells may be injured, which could alter the chemistry of the bloodstream. Further still, withdrawing blood from an infant whose blood system may total 30 to 40 milliliters (ml) blood could create a serious blood deficiency. Multiple blood withdrawals, even in minute amounts, could exsanguinate and thus traumatize the infant's system.
Separating microscopic components from fluids by dialysis is also well known to the art. Kirk-Othmer in Encyclopedia of Chemical Technology, Third Edition, Vol. 7, John Wiley & Sons, New York (1979) at page 564 defines dialysis as a membrane transport process in which solute molecules are exchanged between two liquid phases. The process proceeds in response to differences in chemical potentials between the liquids. There is usually little difference in pressure between the two phases. The membrane separating the liquids permits a diffusional exchange between at least some of the molecular species present while effectively preventing any convective exchange between, or comingling with, the solutions. Thus, in basic principle, the two solutions will come into equilibrium, i.e., a state of balance or equality, across a semi-permeable membrane. However, large molecular structures in the fluid generally will not traverse the semipermeable membrane and do not equilibrate across the membrane.
Dialysis has found many uses in the prior art ranging from biotechnological applications, such as blood dialysis in kidney machines, to industrial applications, i.e., fermentation fluid analysis, chemical separations and chemical analysis.
By far, the largest contemporary use of dialysis involves the treatment of blood, particularly associated with hemodialysis (Kirk-Othmer, supra at page 574). Much of the prior art involving analysis by dialysis is directed to blood analytical procedures. Examples of this procedure follow.
U.S. Pat. No. 4,016,864 to Sielaff et al is generally related to a diffusable tubular membrane in the form of a cathether which is introduced percutaneously into the bloodstream and serves as a conduit for carrier gas in blood gases. Equilibration is allowed to occur between the blood gases and the carrier gas through the membrane. The equilibrated gas is then removed from the diffusable membrane to another area for analysis by displaced volume or reduced pressure.
U.S. Pat. No. 4,156,580 to Polanyl is directed to a continuous blood gas monitoring system. The object behind this invention is to analyze components in a fluid mixture by employing diffusion of the component to be determined to a membrane. The apparatus comprises a probe, a circulating test fluid, and a gas measuring device. The probe is preferably a tube or catheter dwelling in the fluid. A portion of the distal end of this tube is covered with a thin membrane of gas permeable and blood impermeable membrane. The membrane is wound around the outside of the probe tube in spiral fashion.
U.S. Pat. No. 4,265,249 to Schindler et al is directed to an apparatus for the continuous chemical analysis of body fluids. The surface of the catheter is partially coated with a semi-permeable filter membrane. A plurality of channels are provided underneath the membrane which provide a fluid flow path for the material to be analyzed.
U.S. Pat. No. 4,311,789 to Nylen et al discloses a method for measuring the content of a low-molecular weight compound in a complex fluid, such as blood, by placing a dialyzer in contact with a complex fluid. A fraction of the fluid is passed through a semi-permeable membrane of the dialysis, contacted with a dialysis fluid and measured. The dialyzer enters the reference fluid container, such as a blood vessel, at one point and exits at another.
U.S. Pat. No. 4,221,567 to Clark et al is directed to a system for sampling and determining chemical substances in a fluid. A probe containing a liquid is inserted into a fluid matrix containing the diffusible chemical substances to be sampled and monitored. The probe is constructed of a permeable membrane. Within the probe is a tube constructed from materials such as stainless steel or glass. An opening in the tube connects the chambers of the tube and the probe. The probe containing the test fluid is placed in a fluid matrix and purportedly absorbs the chemical substances diffusing through the permeable membrane until equilibrium is reached. The equilibrated fluid is then passed through the opening in the tube and removed therefrom for analysis.
U.S. Pat. No. 3,512,517 to Kadish et al is directed to a means and apparatus for continuously monitoring blood glucose concentrations. One embodiment (FIG. 7) discloses an intravenous dialyzing catheter wherein the blood component to be measured passes through the dialyzing membrane of the catheter and is directly mixed with the analytic reagent. The blood proteins and formed elements do not pass through the dialyzing membrane and purportedly are never removed from the patient. This embodiment permits the monitoring of blood chemistry without actually removing the whole blood from the body. The catheter includes an outer dialyzing membrane and an inner tubing. The material used for the membrane is suitable for dialyzing glucose and other dialyzable blood components from the whole blood, removing the blood proteins and formed elements, i.e., white cells, red cells and platelets from the blood. A specific example is polyethylenevinylpyrrolidone, sold under the trademark PERMION-300 by Radiation Application, Inc. The dialyzed component and an enzyme reagent (for preventing coagulation) are mixed within the catheter and removed for analysis.
U.S. Pat. No. 3,572,315 to Cullen is directed to an apparatus for withdrawing gaseous constitutents from a liquid for analysis of the gaseous constitutents. More specifically, the invention includes a catheter which comprises a cannula having a gas permeable but liquid impervious membrane at the distal end and subatmospheric pressure means connectable with the opposite end for inducing gaseous flow from the blood stream through the cannula.
U.S. Pat. No. 3,640,269 to Delgado is directed to apparatus which is inserted in a living organism, such as the brain, which can pass fluids from or to the organism. Part of the apparatus includes a porous application bag for the displacement of fluids into or out of the system.
Thus, there are known several methods for determining components, specifically gas components, in the bloodstream. These methods employ reaching the equilibrium condition between a body fluid and an external fluid through a membrane followed by analytical determination of the concentration of the gas component in the external fluid. Such methods often involve the use of a hard probe-like apparatus which is often difficult to insert into the blood vessel and thus quite time consuming.
Methods for analyzing fluids by the use of dialysis in the industrial fields are also known to the art. For example, U.S. Pat. No. 4,267,023 to Frant et al is directed to measuring gases, such as sulfur dioxide, in the atmosphere by means of a chemically integrating dosimeter, composed in part of permeable membranes, which makes time integrated exposures to various gases in the atmosphere.
U.S. Pat. No. 4,240,912 to Stumpf et al is directed to an immersion dialyzer specifically for measuring the content of substrates in a sterile medium.
U.S. Pat. No. 3,830,106 to Gardner et al discloses a device for use in sampling components in liquids or gaseous materials by dialysis from the liquids. A primary purpose of this device is in fermentation-type reactions.
Even with the abundance of prior art literature directed to analysis by dialysis, it has long been desirable to provide a simple, safe and efficient manner for separating a low molecular weight compound out of a complex medium for analysis. The present invention provides such a method and apparatus.